It is well known that porous hydroxyapatite exists in a human body. For example, the porous hydroxyapatite is a component of bone and teeth. Therefore, recently, the porous hydroxyapatite is focused as a raw material for bioceramics and many studies have been performed on the porous hydroxyapatite. On the other hand, fine powders of hydroxyapatite which are not porous are industrially manufactured and sold as raw materials for the porous hydroxyapatite, food additives (as calcium triphosphate), stabilizers for polymerization, catalysts and so on.
As known porous hydroxyapatites, (1)spherical apatite, (2)porous apatite, (3)hollow calcium phosphate, (4)granules of calcium phosphate compound, (5)porous bone supplement of calcium phosphate, (6)porous spherical calcium phosphate and so on are reported. The followings are outlines of the above known porous hydroxyapatites.
(1) As the spherical apatite, Japanese laid-open patent publication No.3-16906 entitled "Spherical apatite and manufacturing method thereof and porous structure molded articles" can be exemplified.
This prior art is directed to a spherical apatite, which is comprised of calcium phosphate having its composition of Ca/P molar ratio of 1.4-1.8 and a specific gravity of 3.00-3.17. The spherical apatite has features of a true spherical structure, and a minute and high mechanical strength. However, since the spherical apatite is minute, it has a defect that a percentage of voids is extremely low.
Manufacturing method of the spherical apatite is that a slurry comprising hydroxyapatite as its main component is dried and powdered to prepare aggregates of primary apatite particles, preferably, spray dried to form spherical particles, and then the prepared aggregates of primary apatite particles are fused in a flame of 1500.degree. C. or more so as to obtain the spherical apatite.
The prior art discloses that an apatite of porous structure can be obtained by mixing an adhesive to the aforementioned spherical apatite, pressure molding, and then calcinating in the flame of 1500.degree. C. or more, however, the percentage of voids of the thus obtained porous structure in Examples is 28%, which is a very low value, and therefore, it can not be said that the obtained porous structure has high percentage of voids.
(2) As the porous apatite, Japanese patent publication No.2-14311 entitled "A method for manufacturing a porous apatite" can be exemplified.
Claim 1 of the patent publication describes as follows: "A method for manufacturing a porous apatite which comprises blending calcium carbonate powders to calcium hydrogenphosphate.2H.sub.2 O or an anhydride thereof so that the Ca/P molar ratio becomes 1.50-1.67 and hydrating them by adding water".
Since the obtained porous structure is not a fine particle, but cured in the whole body by hydration reaction. There is a description in Examples that a water-cured apatite of a single phase having a void volume of 71-76% was obtained. However, the obtained apatite has a chemical formula Ca.sub.10 -Z(HPO.sub.4 (PO.sub.4).sub.6 -Z(OH).sub.2 -Z.nH.sub.2 O, wherein Z=O, and therefore, has a crystalline water. Therefore, the obtained apatite is not a hydroxyapatite. It is described in the specification that the hydroxyapatite expressed by the formula Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 can be obtained by calcinating the water-cured apatite at 1000-1350.degree. C. and the void volume, which corresponds to a percentage of voids, of the hydroxyapatite was lowered compared to that of before the calcination, and the void volume of the hydroxyapatite obtained in Examples is 45-50%, which is very low level. Although it is described in the specification that a higher range of the void volume can be controlled and obtained, there is no description regarding the value of the void volume of the hydroxyapatite being more than 45-50% and a method for manufacturing the hydroxyapatite having such high void volume.
Furthermore, all of Examples 1-4 and Comparative examples perform the hydration reaction in the Pyrex glass tube with a cap under conditions of an inner temperature being 50.degree. C. or 80.degree. C. It is described in the specification that according to a reaction scheme, 1 mol of carbon dioxide may be generated with respect to 1 mol of calcium carbonate as a raw material. Therefore, it is clear that inner pressure of the Pyrex glass tube with the cap is very high compared with the atmospheric pressure, and it can be said that the hydration reaction is analogous to a reaction performed in an autoclave under pressure. Moreover, there is no description with respect to the specific calcium hydrogenphosphate.2H.sub.2 O or the specific calcium carbonate to be used.
(3) As the hollow calcium phosphate, Japanese laid-open patent publication No.63-198970 entitled "Hollow body of calcium phosphate" can be exemplified.
This laid-open publication is directed to a hollow sphere with open pores, but not directed to a porous structure, and the specific area described in the specification is 1-6 m.sup.2 /g, which is far less than 10 m.sup.2 /g.
As a manufacturing method, a method of mixing calcium phosphate and an organic foaming agent, foaming the mixture and calcinating at 900-1400.degree. C. is described.
(4) As the granules of calcium phosphate compound, Japanese laid-open patent publication No.1-230412 entitled "Granules of calcium phosphate compound" can be exemplified.
This laid-open publication is directed to granules, but not to a porous structure. Furthermore, the disclosed real surface area (specific surface area) is a very low value, 0.02-0.05 m.sup.2 /g.
As a manufacturing method, it is described that the granules are prepared by making particles with the hydroxyapatite and an organic binder and then removing the organic binder by sintering. As another method, it is described that, instead of the organic binder, a binder of apatite sol obtained by a reaction in a non-aqueous solvent is used so as to make particles, and the particles are dried and sintered. Therefore, it is essential that the organic binder or non-aqueous solvent should be removed.
(5) As the porous bone supplement of calcium phosphate, Japanese patent publication No.1-49501 entitled "Porous bone supplement of calcium phosphate" can be exemplified.
The porous bone supplement of calcium phosphate obtained by the publication has a large porous structure of more than several mm.
As a method for preparing the porous structure, it is described that a heat decomposable beads such as hydroxyapatite powder, polystyrene beads and so on and a forming agent such as aqueous solution of hydrogen peroxide are wet mixed, then foamed and dried in the drier, and the thus obtained dried materials are heat decomposed and sintered at 900-1400.degree. C. under the specific temperature-raising condition.
(6) As the porous spherical calcium phosphate, Japanese patent publication No.4-44606 entitled "Method for manufacturing porous spherical calcium phosphate" can be exemplified.
It is described in the specification that the porous spherical calcium phosphate obtained in the publication has micropores of a close-cropped or spherical form having a specific surface of 1-50 m.sup.2 /g, a particle diameter of 1-100 .mu.m, and a micropore diameter of 0.01-0.5 .mu.m. The specific surface of the hydroxyapatite disclosed in Examples is 5 m.sup.2 /g, which is a very low surface area. The publication also describes a spherical form of porous calcium phosphate in which the diameter of micropores is enlarged by sintering the particle at 1100.degree. C., however, since, generally, the specific surface is believed to be lowered after heat treatment (sintering), the specific surface is supposed to be 5 m.sup.2 /g or less. Regarding porous spherical calcium phosphate which is composed of .beta.-tricalcium phosphate, not a hydroxyapatite, it is merely described that the specific surface is 10 m.sup.2 /g, which is higher than that of the above mentioned hydroxyapatite. Therefore, it can not be said that the porous spherical calcium phosphate composed of hydroxyapatite having the specific surface of 50 m.sup.2 /g can be prepared easily.
As methods of manufacturing the porous spherical calcium phosphate, a method is described that 1 mol of water soluble calcium salt, 1-1.2 mol of a calcium ion complexing agent and 0.5-1 molar of water soluble phosphate are mixed, the pH of the mixture is adjusted to 5-11, then hydrogen peroxide is added to the mixture so that the concentration of the hydrogen peroxide becomes 1-20% by weight, and the mixture is heat reacted at 50-100.degree. C. so as to prepare the porous spherical calcium phosphate, and further, heat treatment (sintering) at 900-1500.degree. C. is also described. It is necessary that by-products of the reaction (salts such as NaCl) and the calcium ion complexing agent should be removed by washing with water. Furthermore, when the value of the specific surface becomes high, there is a tendency that these impurities are difficult to be separated. Therefore, it is supposed that the porous spherical calcium phosphate in which the impurities are remained are apt to be obtained.
The conventional method of manufacturing the porous hydroxyapatite is mainly that fine particles of hydroxyapatite having known plate-like, needle-like, spherical form and so on are aggregated, so as to obtain porous structures caused by the vacancy made by the particles or aggregates. Therefore, since the influence of the fine particles of the raw materials is significant, the obtained porous hydroxyapatite is limited to that having the above mentioned defects. As a major method for enlarging the percentage of voids, the foaming agent, organic spherical compound and organic binder are combined. However, since these compounds are inherently unnecessary for porous hydroxyapatite, a process for removing these compounds such as calcination is required. Moreover, since in the calcination process, the raw materials, i.e., fine particles of the hydroxyapatite, are sintered each other, and as a result, the specific surface is decreased. If the additives are not removed by calcination and so on, the specific surface and the percentage of voids can be lowered compared to the case where the additives are not added.
In a method for preparing fine particles by spray drying using a mere slurry of the particles in the solvent, the thus obtained particles tends to be broken down. Therefore, since the binders are required, there are the same defects as those of the case where the percentage of voids is increased as mentioned above.
There is a method for obtaining the porous hydroxyapatite by calcinating or fusing the fine particles of the calcium phosphate other than hydroxyapatite instead of the fine particle of the hydroxyapatite. However, since the fine particles of the raw materials are sintered each other as mentioned above, the specific surface can be lowered.
The followings are methods for preparing hydroxyapatite, however, these methods are not related to porous hydroxyapatite.
(7) As a report regarding calcium phosphate compounds which have high specific surface, Japanese laid-open patent publication No.5-68442 entitled "Sustained-release material of calcium phosphate" is exemplified.
Although claim 1 describes "Sustained-release material of calcium phosphate obtained from adsorbing at least one material to be released which is selected from the group consisting of deodorants, bactericides, agricultural medicines, fungicides and insecticides to a base composed of hydroxyapatite having specific surface of 100-250 m.sup.2 /g by BET method", there is no description regarding porous hydroxyapatite.
A method of manufacturing hydroxyapatite described in Example 1 is a known method of adding a concentrated phosphoric acid aqueous solution of 40% to a calcium hydroxide aqueous dispersion of 10% concentration.
(8) A method for preparing the hydroxyapatite by adding phosphoric acid gradually to the calcium hydroxide aqueous suspension:
The aforementioned (7) is exemplified. This method has advantages that by-products other than calcium phosphate cannot be produced, and therefore, this is an excellent method in obtaining the mixture of hydroxyapatite and tricalcium phosphate. Generally speaking, hydroxyapatite obtained by this method has a needle-like, plate-like and spherical form of super fine particles of 0.1 .mu.m or less, and therefore, the hydroxyapatite has many defects that not only the dehydration and filtration of the reactant is poor (very low rate of filtration), but also it is not easy to wash due to the poor filtration ability, and dried powders tend to aggregate. Moreover, there are defects that the unreacted calcium hydroxide tends to remain, and since the remained calcium hydroxide reveals strong alkalinity, the calcium hydroxide, which is remained, can give inferior effects to the materials to be adsorbed. As improved methods, for example, a method that, after the reaction, the unreacted calcium hydroxide is removed by washing and/or heat treating at a higher temperature where the calcium hydroxide can be decomposed, preferably, at 900.degree. C. or more, and a method of raising a reactivity of calcium hydroxide and phosphoric acid by a wet grinding-crushing by the use of a crushing medium such as glass beads, are reported.
(9) Many methods improving the above mentioned defects (8) are reported.
The improved methods such as water-heating synthetic method including a method for, after the reaction is completed, heat treating the reaction mixture at a high temperature of 80.degree. C. or more for a long period of time or heating the reaction mixture in a closed vessel (autoclave) for a long period of time, a sintering synthetic method for, after preparing, synthesizing by sintering the prepared product at a temperature being 600.degree. C. or more (preferably 900.degree. C. or more), where calcium hydroxide can decompose, and a method for increasing the reactivity by grinding and crushing at the time of reacting, and so on are exemplified. By these methods, hydroxyapatite can be obtained, however, these methods have many defects: not only the process becomes complicated, but also specific surface is decreased by heat treatment, percentage of voids is decreased by sintering and break down of the porous material by grinding, and so on.
(10) Methods for preparing hydroxyapatite by sintering an intermediate which is prepared by hydration reaction of calcium salts which are water insoluble or difficult to dissolve in water, and phosphates.
A method using calcium carbonate as the calcium salt and calcium hydrogenphosphate.2H.sub.2 O as the phosphate is also reported. As this method, aforementioned (2) can be exemplified and the method has the same defects as described. A method in which the reaction is performed in a water under stirring is reported.
For example, Japanese laid-open patent publication No.62-223010 entitled "Method for manufacturing hydroxyapatite" can be exemplified. However, there are no examples regarding combination of calcium carbonate and calcium hydrogenphosphate.2H.sub.2 O nor description that a specific hydroxyapatite can be manufactured. Furthermore, Japanese patent publication No.58-30244 entitled "Method for manufacturing hydroxyapatite containing carbonic acid" can be exemplified. However, this method is characterized in that ammonium hydroxide is used in combination, and is a method for obtaining hydroxyapatite containing carbonic acid, which is different from hydroxyapatite. Moreover, it is described in Angew. Chem. internat. Edit./vol.5 (1966)/No.7, pp669-670 that, into the slurry of calcium carbonate of calcite crystal and calcium hydrogenphosphate.2H.sub.2 O, an air purified with KOH was introduced, several days after at 37.degree. C., carbonate apatite, 5/4[Ca(PO.sub.4).sub.2 (HPO.sub.4).sub.0.4 (CO.sub.3).sub.0.6 ], was obtained as a product, and that the feature of X-ray diffraction of the product is analogous to that of octacalcium phosphate. This product is different from the hydroxyapatite of the present invention.
(11) As a report regarding hydroxyapatite with high specific surface, Journal of Colloid and Interface Science, Vol.55, No.2(1976) pp409-p414 describes that hydroxyapatite having the specific surface of 198 m.sup.2 /g by BET method was obtained by setting the starting ratio of Ca.sup.2+ /PO.sub.4.sup.3 -- at 1.71, performing the reaction under nitrogen atmosphere at room temperature with stirring to obtain a precipitate, contacting the precipitate, amorphous calcium phosphate with a basic mother liquid for 4 days and then centrifuging the product, dialyzing the product using a membrane tube of Spectropor thereby washing with the distilled water, continuing the dialysis until the pH of the washed water becomes neutral, and subjecting to freeze drying. The product is different from the petaloid porous hydroxyapatite of the present invention.
(12) As a report regarding hydroxyapatite with high specific surface, Inorganic Chemistry (1982), vol.21 No.8, pp3029-3035 describes that a non-stoichiometrically amorphous and crystalline calcium phosphate was obtained by a precipitation reaction by mixing a phosphoric acid solution and a saturated solution of calcium hydroxide under, the pH of the mixture controlled at 7.00, 7.40, 8.25, 9.75 and 10.00. In this case, all the calcium carbonate which was produced upon the preparation of the saturated calcium hydroxide solution was removed so that the content of the calcium carbonate in the reaction system is as small as possible. Therefore, the disclosed method is not a method of manufacturing the hydroxyapatite from calcium carbonate and phosphoric acid, that is the present invention. Furthermore, the produced hydroxyapatite which lacks calcium has the specific surface of 163 m.sup.2 /g by BET method, however, since the pH was adjusted by the mixing ratio of the phosphoric acid solution and the calcium hydroxide saturated solution, the Ca/P ratio of the produced powder becomes 1.40-1.58. Therefore, the hydroxyapatite with a high purity of the present invention can not be obtained.
(13) Methods for preparing hydroxyapatite by a solution reaction by mixing water soluble calcium salts and water soluble phosphate.
The aforementioned (6) is an improved method of this method, however, this method has many defects, such as difficulty in control of the reaction and removal of the by-products.
(14) Methods for preparing hydroxyapatite by preparing amorphous calcium phosphate as an intermediate by hydrolyzing calcium methoxide and organic phosphate compounds in an organic solvent, followed by chemical reaction or sintering and so on.
This method has many defects; expensive raw materials should be used, the reaction process is complicated, reproductivity of the process is difficult since the amorphous calcium phosphate is unstable, and so on.
(15) Method for preparing hydroxyapatite by dry synthetic method in which tricalcium phosphate and calcium salts are reacted in a water vapor of 900.degree. C. or more.
This method has defects that, since the hydroxyapatite is produced by sintering at high temperature, the specific surface and the percentage of voids of the hydroxyapatite are low. There is an improved method in which an excess amount of calcium salts is added, and after the reaction is completed, CaO and others which are produced by the excess calcium salts are removed by washing with water.
(16) As a combination of calcium carbonate and phosphoric acid, Japanese laid-open patent publication No.1-290513 entitled "Method for manufacturing hydroxyapatite" is indicated. However, this method is directed to manufacturing hydroxyapatite with a Ca/P ratio of 1.67 by making an intermediate of tricalcium phosphate (Ca.sub.3 (PO.sub.4).sub.2) whose Ca/P ratio is 1.5 and by reacting calcium carbonate with phosphoric acid, followed by adding calcium hydroxide to the intermediate in the closed vessel. Therefore, this method is not a method of manufacturing hydroxyapatite from calcium carbonate and phosphoric acid.
A method for preparing calcium phosphate having an atomic molar ratio of 0.5-1.5 from calcium carbonate and phosphoric acid is known, and as a calcium phosphate, calcium dihydrogen phosphate of Ca/P=0.5, calcium hydrogenphosphate and calcium hydrogenphosphate.2H.sub.2 O of Ca/P=1, tricalcium phosphate of Ca/P=1.5 and so on are exemplified.
In the conventional manufacturing method of porous hydroxyapatite and hydroxyapatite, there is no report regarding fine particles of porous hydroxyapatite which can satisfy all the properties of adjustable high percentage of voids, high specific surface and specific diameter of micropore and a manufacturing method thereof. Moreover, there is no report that the porous hydroxyapatite can retain superior properties and is easy to handle, and is a fine particle having superior dispersibility and specific diameter of the particle.
Thus, fine particles of porous hydroxyapatite which can satisfy all the properties of high percentage of voids, high specific surface and specific diameter of the micropore and a method for manufacturing thereof are required. Furthermore, since the porous hydroxyapatite can retain a superior properties and is easy to handle, and is a fine particle having superior dispersibility and specific diameter of the particle, the particles are expected to be used, not only as raw materials for bioceramics, but also in other many fields. As the fields for application, carriers for catalysts, pharmaceuticals, agricultural medicines, microbials, biologicals and peroxides, plant growth agents, absorbents of olefins, absorbents of ultraviolet, adsorbents, sustained-release materials, water-absorbing agents, raw materials for ceramics, many kind of carriers, filtering agents, filtering aids, growth for microbials, biological materials, drying agents, fragrants and other supports or raw materials thereof are exemplified. It is also expected to be used in plastics, rubbers, paints, inks, sealing materials, paper manufacture, fibers and films.
After extensive and intensive studies, the present inventors have found out novel fine particles of petaloid porous hydroxyapatite and method for manufacturing thereof, and thus accomplished the present invention based on these findings.